The present invention relates to therapeutic agents for glomerulosclerosis containing 1xcex1,3xcex2-dihydroxy-20xcex1-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10 (19)-pregnatriene (hereinafter also referred to as 22-oxa-1xcex1,25-dihydroxyvitamin D3) as an active ingredient.
Glomerulosclerosis is induced by irreversible progress of various glomerular diseases of different etiologies and histopathological pictures. It is mainly pathologically characterized by mesangial cell proliferation or increased mesangial matrix accompanied by atrophy, degeneration or collapse of glomerular cells. Examples of the etiologies of glomerulosclerosis include IgA nephropathy or diabetic nephropathy, which were reported to be characterized by mesangial cell proliferation or increased mesangial matrix. In order to establish a therapy for glomerulosclerosis, it seems important to clarify the mechanism of the onset or to understand the pathology. Thus, efforts have been made to develop experimental nephritis models that experimentally induce lesions with mesangial cell proliferation and mesangial matrix production, and a rat model of anti-Thy 1 antibody-induced nephritis was prepared (Bagchus, W. M. et al., Lab. Invest, Vol. 55, No. 6, pp. 680-687, 1986). This model shows glomerular nephritis with mesangial cell proliferation and mesangial matrix production caused by the reaction between Thy 1 antigen existing as a membrane protein in mesangial cells and an antibody against it, and drug efficacy tests in this model were reported (Masashi Haraguchi et al., Kidney International, Vol. 51 (1997), pp. 1838-1846).
Drugs such as antitumor agents or immunosuppressive agents based on activated vitamins D3 (i.e., 1,25-dihydroxyvitamins D3) have been developed since they were reported to have not only a calcemic action but also a differentiation-inducing effect (Abe E. et al., Proc. Natl. Acad. Sci. USA, Vol. 78, No. 8, pp. 4990-4994, 1981). 1,25-Dihydroxyvitamins D3 were also reported to have an antiproliferative effect on human mesangial cells (Weinreich T. et al., American Journal of Kidney Diseases, Vol. XVIII, No. 3, 1991, pp. 359-366). However, it was difficult to use 1,25-dihydroxyvitamins D3 for antiproliferative purposes due to hypercalcemia.
Thus, vitamin D3 derivatives with a low calcemic action were researched and some derivatives were developed. One of such vitamin D3 derivatives is 22-oxa-1xcex1,25-dihydroxyvitamin D3, which was reported to show a differentiation-inducing effect without causing hypercalcemia (Abe J. et al., FEBS Lett., Vol. 226, No. 1, pp. 58-62, 1987). Japanese Patent No. 2854600 describes that 22-oxa-1xcex1,25-dihydroxyvitamin D3 inhibits urinary protein excretion so that it is useful as a therapeutic agent for glomerulonephritis.
However, nothing has been shown about the effect of 22-oxa-1xcex1,25-dihydroxyvitamin D3 on mesangial cell proliferation or mesangial matrix production.
An object of the present invention is to provide pharmaceutical compositions having the effect of inhibiting mesangial cell proliferation or mesangial matrix production with a low calcemic action.
As a result of careful studies to attain the above object, the inventor accomplished the present invention on the basis of the finding that 22-oxa-1xcex1,25-dihydroxyvitamin D3 inhibits mesangial cell proliferation without causing hypercalcemia and also inhibits the expression of collagen in a rat model of anti-Thy 1 antibody-induced nephritis.
Accordingly, the present invention provides therapeutic agents for glomerulosclerosis containing 1xcex1,3xcex2-dihydroxy-20xcex1-(3-hydroxy-3-methylbutyloxy)-9,10-seco-5,7,10 (19)-pregnatriene as an active ingredient.
Therapeutic agents for glomerulosclerosis of the present invention can be used as pharmaceutical compositions for inhibiting mesangial cell proliferation or excessive mesangial matrix production.
Therapeutic agents for glomerulosclerosis of the present invention can also be used as pharmaceutical compositions for inhibiting the overexpression of collagen in the mesangium.
The present application claims priority based on Japanese Patent Application No. 128566/1999, the disclosure of which is entirely incorporated herein as reference.